Human cytomegalovirus (HCMV, a -herpesvirus) causes lifelong, persistent/latent infection that is largely asymptomatic in healthy persons, but can induce serious disease if host immunity is nave or compromised. HCMV encodes for >170 viral proteins, more than half which function to modulate host innate and adaptive immune defenses. Characterizing the structural and molecular basis of the interactions that occur between these HCMV and host proteins is crucial to facilitate vaccine and antiviral drug development. NK cells are crucial in controlling viral infection and HCMV has evolved several mechanisms to inhibit NK cell activation. In this proposal we will study the gene product UL141, encoded by virulent strains of HCMV, that we hypothesize has evolved to modulate immune signaling networks by targeting both ligands for NK cell receptors, as well as the TNF death receptors. UL141 inhibits expression of TRAIL-DR as well as CD155, an NK cell activating ligand. Together with HCMV gene product US2, UL141 also downregulates CD112, a second ligand for the NK cell activating receptor DNAM-1. In addition, we speculate that UL141 mimics the function of TIGIT, an immunoreceptor that also inhibits NK cell activation. Uncovering how UL141 crosstalks with signaling networks comprised of Ig and TNF family proteins will yield valuable information regarding how these non-canonical binding interactions function to regulate host immunity.